Caplacizumab, an investigational anti-von Willebrand factor humanized single-variable-domain immunoglobulin, led to a more rapid resolution of thrombotic thrombocytopenia purpura (TTP) episodes than placebo, according to results of the phase II, randomized, controlled TITAN trial published in The New England Journal of Medicine. However, caplacizumab was also associated with an increased tendency toward mild bleeding.

Acquired TTP is a life-threatening condition caused by severe deficiency of ADAMTS13, which can lead to the accumulation of ultra-large von Willebrand factor multimers. Treatment of TTP includes rapid initiation of plasma exchange (to remove auto-antibodies and replenish ADAMTS13 activity) and immunosuppressive therapy, but the TITAN researchers noted that these treatments take time to achieve resolution of the disease: “Even when patients have a response to therapy, they are at risk for further microvasculature thrombosis, which is unpredictable in its onset, severity, and outcome.”

In the TITAN trial, Flora Peyvandi, MD, PhD, associate professor of internal medicine at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Italy, and colleagues investigated whether caplacizumab, which targets the A1 domain of von Willebrand factor and is designed to block further platelet aggregation in the microvasculature, could be an effective, rapid-onset therapy for acquired TTP.

“A rapid control of the micro-thrombotic component is crucial for the treatment of acquired TTP because microvascular thrombosis is associated with significant mortality and morbidity,” Filip Callewaert, PhD, corresponding author of the study told ASH Clinical News. “Caplacizumab could be the first targeted therapy for acquired TTP.”

The TITAN trial enrolled 75 adult patients from 56 centers worldwide between October 2010 and January 2014. Adult patients with an acute episode of acquired TTP were eligible for inclusion if they had a platelet count <100,000/m3, had no active bleeding, and required plasma exchange. Patients were randomized 1:1 to receive once-daily 10 mg caplacizumab (n=36) or placebo (n=39) in addition to plasma exchange and immunosuppressive therapy. Treatment with caplacizumab or placebo continued for 30 days after the last plasma exchange, with a maximum treatment duration of 90 days.

The median time to response (defined as confirmed normalization of the platelet count) was three days for the caplacizumab cohort (95% CI 2.7-3.9) compared with 4.9 days for the placebo group (95% CI 3.2-6.6) – a 39 percent reduction (95% CI 1.28-3.78; p=0.005).

At one-month of follow-up, complete remission (defined as normalization of the platelet count and an absence of exacerbations after the initial course of daily plasma exchange) was observed more frequently with caplacizumab than placebo (81% vs. 46%; p value not available).

Three of the caplacizumab-treated patients had exacerbations of disease activity (defined as recurrent thrombocytopenia within 30 days after the end of daily plasma exchanges that required re-initiation of daily exchanges), compared with 11 of the placebo-treated patients. “The number of days of plasma exchange also was reduced,” Dr. Callewaert added. “This means that the patient is discharged from the hospital sooner and is less dependent on plasma exchange with its associated complications.”

Following cessation of the study drug, eight patients who had received caplacizumab relapsed – seven of them within 10 days of cessation – while no patients in the placebo cohort relapsed.

“This between-group difference suggests that, among patients who were destined to have an exacerbation, it occurred during study-drug administration in the placebo group, whereas caplacizumab may have delayed the exacerbation until after the period of study-drug administration,” the authors observed.

The majority of patients who experienced disease exacerbation or had a relapse early after cessation of the study drug also had continuing low ADAMTS13 levels (<10%), indicating unresolved autoimmune activity and suggesting that ADAMTS13 activity could be used to predict patients at risk for relapse and could guide decisions about the duration of caplacizumab treatment, in addition to guiding immunosuppressive treatment.

Adverse events (AEs) occurred in 97 percent of caplacizumab-treated patients (n=34/35) and all placebo-treated patients (n=37), the most common of which were headache and epistaxis. Most of the reported AEs were considered unrelated to study treatment. Two deaths occurred during the study, both of which were in the placebo group.

Caplacizumab-treated patients were more likely to have bleeding-related AEs, compared with the placebo cohort (54% vs. 38%; p value not available). Serious bleeding-related AEs were reported in two patients in each study group: subarachnoid and retinal hemorrhage and metrorrhagia in the caplacizumab group and cerebral hemorrhage and hematuria in the placebo group.

Similarly, immune-related AEs were reported more often in the caplacizumab than in the placebo group (49% vs. 32%; p value not available).

“On the basis of its pharmacologic effect, we expected that caplacizumab treatment would be associated with an increased risk of bleeding,” the authors explained. “Although bleeding events were observed more frequently in the caplacizumab group than in the placebo group, these events were generally mild and did not require treatment.”

Ultimately, Dr. Peyvandi and co-authors concluded, “caplacizumab prevents further platelet aggregation more rapidly than conventional treatment alone, which could potentially prevent short- and long-term end-organ injury due to ischemia.” They noted, however, the limitation that this observation may have been confounded by the diluting effect of plasma exchange.